Therapy for collagen diseases by using chemokine antagonists

使用趋化因子拮抗剂治疗胶原疾病

• 批准号: 14570414
• 负责人: HASEGAWA Hitoshi
• 金额: $ 2.24万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570414/
• 关键词: Chemokines; Chemokine antagonists; Collagen diseases; MRL; lpr mouse; lpr mouse

The use of receptor antagonists for chemokines is an alternative approach to blocking cnemokine actions and has the potential to provide novel therapeutics for autoimmune diseases. The NH_2-terminally truncated MCP-1 or fractalkine analogues were converted to secreting forms, inserted into the pCXN2 expression vector and transfected into a non-metastatic fibroblastoid cell tin. MRL/N-1. MCP-1-antagonist-or fractalkine-antagonist-transfected MRL/N-1 cells were injected subcutaneously into MRL/lpr mice aged 7 wk (before the initiation of lupus nephritis) and 12 wk (at the early stage of the disease) After 8 weeks, MCP-1-antagonist-and fractalkine-antagonist-bearing mice showed markedly diminished infiltration of macrophages and T cells, glomerular hypercellularity, glomerulosclerosis, crescent formation and also vasculitis compared with control mice. In addition, MCP-1-antagonist-bearing mice ameliorated the progression of sialadenitis compared with control mice. To determine whether SLC antagonist inhibits the development of chronic GVHD, chronic GVHD was induced by injecting DBA/2 spleen cells into (C57BL/6 X DBA/2) F1 mice. Total numbers of spleen cells and host B cells, serum levels of IgE, and of total IgG and IgG1 of anti-DNA antibodies in SLC antagonist-treated GVHD mice were significantly lower than those in control PBS-treated GVHD mice. This result suggests that SLC antagonist has beneficial effects for the prevention of chronic GVIHD.

趋化因子受体拮抗剂的使用是阻断趋化因子作用的另一种方法，并有可能为自身免疫性疾病提供新的治疗方法。将NH_2端截短的MCP-1或Fractalkine类似物转化为分泌型，插入pCXN 2表达载体，转染非转移性成纤维细胞。MRL/N-1。将转染MCP-1拮抗剂或Fractalkine拮抗剂的MRL/N-1细胞皮下注射到7周龄的MRL/lpr小鼠中，（狼疮肾炎开始前）和12周（在疾病的早期）8周后，携带MCP-1拮抗剂和Fractalkine拮抗剂的小鼠显示巨噬细胞和T细胞的浸润、肾小球细胞过多、肾小球硬化，新月体形成和血管炎。此外，与对照小鼠相比，MCP-1拮抗剂荷瘤小鼠改善了涎腺炎的进展。为了确定SLC拮抗剂是否抑制慢性GVHD的发展，通过将DBA/2脾细胞注射到（C57 BL/6 X DBA/2）F1小鼠中来诱导慢性GVHD。SLC拮抗剂治疗组小鼠的脾细胞总数、宿主B细胞总数、血清IgE水平、抗DNA抗体的总IgG和IgG 1水平均显著低于对照组。这一结果表明SLC拮抗剂对预防慢性GVIHD具有有益作用。

项目成果

Hasegawa, H., Kohno, M., Nomura, T., Sasaki, M., Yoshie, O., Fujita, S.: "CCR7 chemokine receptor expression on normal lymphocyte subsets and adult T-cell leukemia cells."Leucocyte Typing VII (Mason, DY et al. Eds.)(Oxford University Press). 255-258 (2002

Hasekawa, H.、Kohno, M.、Nomura, T.、Sasaki, M.、Yoshie, O.、Fujita, S.：“正常淋巴细胞亚群和成人 T 细胞白血病细胞上的 CCR7 趋化因子受体表达。”白细胞分型

Hasegawa, H. et al.: "Antagonist of monocyte chemoattractant protein 1 (CCL2) prevents the initiation and progression of lupus nephritis and renal vasculitis in MRL/1pr mice"Arthritis and Rheumatism. 48. 2555-2566 (2003)

Hasekawa, H. 等人：“单核细胞趋化蛋白 1 (CCL2) 的拮抗剂可预防 MRL/1pr 小鼠狼疮性肾炎和肾血管炎的发生和进展”关节炎和风湿病。

Nakatani, K., Fujii, H., Hasegawa, H.et al.: "Endothelial adhesion molecules in glomerular lesions : Association with their severity and diversity in lupus models."Kidney International. in press.

Nakatani, K.、Fujii, H.、Hasekawa, H.等人：“肾小球病变中的内皮粘附分子：与其在狼疮模型中的严重性和多样性的关联。”肾脏国际。

Kohno, M., Hasegawa, H.: "Chemokines and autoimmune diseases"Recent Research Developments in Immunology. 4. 115-126 (2002)

Kohno，M.，Hasekawa，H.：“趋化因子和自身免疫性疾病”免疫学的最新研究进展。

Haseeawa, H.: "Chemokine antagonist."Rinshomeneki. 40. 668-675 (2003)

Haseeawa, H.：“趋化因子拮抗剂。”Rinshomeneki。